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J. Biol. Chem., Vol. 279, Issue 10, 9504-9511, March 5, 2004

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Role of Iron (II)-2-Oxoglutarate-dependent Dioxygenases in the Generation of Hypoxia-induced Phosphatidic Acid through HIF-1/2 and von Hippel-Lindau-independent Mechanisms^*

Silvia Martín-Puig, Elisa Temes¶, Gemma Olmos||, David R. Jones**, Julián Aragonés, and Manuel O. Landázuri¶¶

From the Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Diego de León, 62, 28006, Madrid, Spain

Hypoxia-inducible factors (HIF-1/HIF-2) govern the expression of critical genes for cellular adaptation to low oxygen tensions. We have previously reported that the intracellular level of phosphatidic acid (PA) rises in response to hypoxia (1% O₂). In this report, we have explored whether components of the canonical HIF/von Hippel-Lindau (VHL) pathway are involved in the induction of PA. We found that hypoxia induces PA in a cell line constitutively expressing a stable version of HIF-1. PA induction was also found in HIF-1- and 2-negative CHO Ka13 cells, as well as in HIF--negative HepaC4 cells. These data indicate that HIF activity is neither sufficient nor necessary for oxygen-dependent PA accumulation. PA generation was also detected in cells deficient for the tumor suppressor VHL, indicating that the presence of VHL was not required for the induction of PA. Here we show that PA accumulation also occurs at moderate hypoxia (5% O₂), although to a lesser extent to that seen at 1% O₂, revealing that PA is induced at the same hypoxia range required to activate HIF-1. Prolyl hydroxylases (PHD) and asparaginyl hydroxylase (FIH) belong to the iron (II) and 2-oxoglutarate-dependent dioxygenase family and have been proposed as oxygen sensors involved in the regulation of HIFs. Chemical inhibition of these activities by treatment with iron chelators or 2-oxoglutarate analogs also results in a marked PA accumulation similar to that observed in hypoxia. Together these data show that PA accumulation in response to hypoxia is both HIF-1/2- and VHL-independent and indicate a role of iron (II)-2-oxoglutarate-dependent dioxygenases in the oxygen-sensing mechanisms involved in hypoxia-driven phospholipid regulation.

Received for publication, September 26, 2003 , and in revised form, December 12, 2003.

^* This work was supported by grants from the Fondo de Investigaciones Sanitarias (CO3/01), and from the Ministerio de Ciencia y Tecnología (SAF 2001-0215). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

Supported by a graduate fellowship from Instituto de Salud Carlos III.

^¶ Supported by a graduate fellowship from Fondo de Investigaciones Sanitarias.

^|| Supported by the Spanish Cardiovascular Network.

^** Present address: Division of Cellular Biochemistry, The Netherlands Cancer Institute Plesmanlaan 121.1066 CX Amsterdam, The Netherlands.

Both authors contributed equally to this work.

Present address: Center for Transgene Technology and Gene Therapy, VIB, KULeuven Campus Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium.

^¶¶ To whom correspondence should be addressed. Tel.: 34-91-5202662; Fax: 34-91-5202374; E-mail: mortiz.hlpr{at}salud.madrid.org.

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